Diabetes causes widespread peripheral sensory and autonomic neuropathy, particularly when blood glucose levels are poorly controlled. Diabetic sensory neuropathy is associated with both negative and positive neurological symptoms. Negative (loss of function) symptoms include reduced vibration perception, compromised light touch and position sense, weakness and depressed tendon reflexes, loss of sensitivity to thermal and noxious stimuli. Negative neurological symptoms are the result of damage to sensory fibers. Positive neurological symptoms comprise neuropathic pain and paresthesias. Pain ranks among the most common debilitating complications of diabetes, yet research in this area has, to a large extent, escaped the attention of investigators. The proposed study will begin to address this gap in knowledge. Streptozotocin- or alloxan-diabetic rats with poorly controlled blood sugar levels are known to be hyperalgesic. A previous neurophysiological study in spontaneously diabetic (BB) rats found an abnormally high incidence of spontaneous action potential discharge originating in the cell bodies of dorsal root ganglion (DRG) neurons. The goal of the present exploratory/developmental (R21) research proposal is to correlate the appearance of hyperalgesia in the spontaneously diabetic BB rat with the emergence of spontaneous action potential discharge in the cell bodies of nociceptive DRG neurons. Furthermore, we will examine the dependence of spontaneous action potential discharge on the contribution of tetrodotoxin-sensitive and tetrodotoxin-resistant voltage-gated sodium currents. The same question will be asked about voltage- gated sodium currents which may contribute to spontaneous action potential discharge in DRG neurons obtained from human patients treated surgically (by ganglionectomy) for intractable neuropathic pain due to nerve injury. Together, the proposed studies are expected to provide new information about the DRG as a peripheral source of neuropathic pain. The results will form the basis of a planned RO1 research proposal.